Galnac conjugated modified oligonucleotides as miR-122 inhibitor having HCV antiviral activity with reduced hyperbilirubinemia side-effect
Inventors
Allerson, Charles R. • Neben, Steven S. • Wright, Timothy
Assignees
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Publication Number
US-12005120-B2
Publication Date
2024-06-11
Expiration Date
Abstract
Described herein are compositions and methods for the inhibition of miR-122 activity. The compositions have certain nucleoside modifications that yield potent inhibitors of miR-122 activity and comprise moieties that facilitate delivery to the liver. The compositions may be administered to subjects infected with hepatitis C virus, as a treatment for hepatitis C virus and related conditions.
Core Innovation
The invention relates to inhibiting miR-122 using an anti-miR-122 oligonucleotide. In particular, a GalNAc-conjugated modified oligonucleotide targeting HCV is disclosed, including an exemplary compound RG6650, linked to an anti-miR-122 oligonucleotide (RG7443) with specified nucleoside and inter-nucleoside linkage pattern including phosphorothioate/phosphodiester linkages.
The background problem addressed is transient hyperbilirubinemia observed with RG-101, attributed to inhibition of conjugated bilirubin transport (MRP2). This motivates screening for alternative miR-122 inhibitors intended to provide miR-122 inhibition while reducing hyperbilirubinemia, and the disclosure includes pharmaceutical compositions and liver uptake supported by ASGPR-affinity ligands such as GalNAc.
The document further describes treatment in subjects with HCV infection using the disclosed miR-122 inhibiting compound, including combination with direct-acting antivirals (DAAs). The disclosed treatment frameworks include specified timing constraints relative to DAA dosing, treatment periods of 12 weeks or less, applicability across HCV genotypes including 1a, 1b, and 2-6, and outcome measures using HCV RNA levels and sustained virological response (SVR).
Structural frameworks described as Structure C and Structure E/F/G/H provide generalized options for ligands, scaffolds, and linkers, together with nucleoside and linkage variations. The disclosure emphasizes modularity of ligand/scaffold/linker components to support liver uptake, including use of ASGPR-affinity ligands such as GalNAc and tuning of linkage and scaffold elements.
Claims Coverage
The independent claim covers a compound having a specified structural formula, or a pharmaceutically acceptable salt, and the independent claim is associated with inventive features including miR-122 inhibition in cells and treatment of HCV infection with DAAs and treatment-duration constraints.
Specified compound structure or pharmaceutically acceptable salt
A compound of the structure [structural formula], or a pharmaceutically acceptable salt thereof.
Inhibiting miR-122 activity by contacting a cell
A method for inhibiting miR-122 activity in a cell by contacting the cell with a compound described in claim 1.
Combining with a direct-acting antiviral for HCV infection within 12 weeks
Treating HCV infection by administering at least one dose of the claim 1 compound together with at least one direct-acting antiviral (DAA) to an HCV-infected subject for a treatment period of 12 weeks or less, where the compound is given as a start dose only and/or an end dose only during the treatment period.
Selecting treatment period duration in defined week ranges
Carrying out the HCV treatment with a treatment period duration selected to be within 2–10 weeks, 4–8 weeks, 2–6 weeks, or 1–4 weeks.
Applying to specified HCV genotypes 1a or 1b
The HCV-infected subject is infected with hepatitis C virus genotype 1a or genotype 1b.
Dose ceiling for treating method
The method further specifies a dose of the compound that is less than or equal to one of the specified mg/kg values (4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5 mg/kg).
Overall, the claim coverage centers on a specific structured miR-122 inhibitor compound or salt and extends to methods of inhibiting miR-122 in cells and treating HCV infection. The treatment method includes combination with direct-acting antivirals within a treatment period of 12 weeks or less, with the miR-122 inhibitor administered as start and/or end dosing, and further restrictions on dosing-related timing, selected week ranges, genotype 1a or 1b, and an explicit dose ceiling.
Stated Advantages
Inhibits miR-122 activity in a cell.
Treats hepatitis C virus (HCV) infection.
Reduced hyperbilirubinemia compared to RG-101 is motivated by the stated attribution of RG-101 transient hyperbilirubinemia to inhibition of conjugated bilirubin transport (MRP2).
Documented Applications
A method for inhibiting miR-122 activity in a cell by contacting the cell with the disclosed compound.
A method for treating hepatitis C virus (HCV) infection in an HCV-infected subject using the claimed compound in combination with at least one direct-acting antiviral (DAA) for a treatment period of 12 weeks or less, with refinements including specified treatment durations, genotypes (1a/1b), and dose ceilings.
Treating hepatitis C virus (HCV) infection in subjects using the disclosed miR-122 inhibiting compound in combination with direct-acting antivirals (DAAs), for treatment periods of 12 weeks or less, including via start dose only and/or end dose only during the treatment period.
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